Transmucosal delivery devices with enhanced uptake

ABSTRACT

The present invention provides methods for enhancing transmucosal uptake of a medicament, e.g., fentanyl or buprenorphine, to a subject and related devices. The method includes administering to a subject a transmucosal drug delivery device comprising the medicament. Also provided are devices suitable for transmucosal administration of a medicament to a subject and methods of their administration and use. The devices include a medicament disposed in a mucoadhesive polymeric diffusion environment and a barrier environment.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/746,168 filed Jun. 22, 2015, which is a continuation of U.S. patentapplication Ser. No. 13/413,112, filed Mar. 6, 2012, which is acontinuation of U.S. patent application Ser. No. 13/184,306, filed Jun.15, 2011, which is a continuation of U.S. patent application Ser. No.11/817,915, filed Oct. 6, 2009, which is a U.S. National Phase ofPCT/US2007/016634, filed Jul. 23, 2007. PCT/US2007/016634 claimspriority to U.S. Provisional Application No. 60/832,725, filed Jul. 21,2006, U.S. Provisional Application No. 60/832,726, filed Jul. 21, 2006,and U.S. Provisional Application No. 60/839,504, filed Aug. 23, 2006.The entire contents of these applications are incorporated herein byreference. This application is also related to U.S. Ser. No. 11/639,408,filed Dec. 13, 2006, and PCT/US2006/47686, also filed Dec. 13, 2006,both of which claim priority to U.S. Provisional Application No.60/750,191, filed Dec. 13, 2005, and 60/764,618, filed Feb. 2, 2006. Theentire contents of these applications are also incorporated herein bythis reference.

BACKGROUND

U.S. Pat. No. 6,264,981 (Zhang et al.) describes delivery devices, e.g.,tablets of compressed powders that include a solid solutionmicro-environment formed within the drug formulation. Themicro-environment includes a solid pharmaceutical agent in solidsolution with a dissolution agent that that facilitates rapiddissolution of the drug in the saliva. The micro-environment provides aphysical barrier for preventing the pharmaceutical agent from beingcontacted by other chemicals in the formulation. The micro-environmentmay also create a pH segregation in the solid formulation. The pH of themicro-environment is chosen to retain the drug in an ionized form forstability purposes. The rest of the formulation can include buffers sothat, upon dissolution in the oral cavity, the pH is controlled in thesaliva such that absorption of the drug is controlled.

US Publication 2004/0253307 also describes solid dosage forms thatinclude buffers that upon dissolution of the solid dosage form maintainsthe pharmaceutical agent at a desired pH to control absorption, i.e., toovercome the influence of conditions in the surrounding environment,such as the rate of saliva secretion, pH of the saliva and otherfactors.

BRIEF SUMMARY OF THE INVENTION

The present invention provides transmucosal devices for enhanced uptakeof a medicament and methods of making and using the same. In someembodiments, the devices generally include a mucoadhesive polymericdiffusion environment that facilitates not only the absorption of themedicament across the mucosal membrane to which it is applied, butadditionally, the permeability and/or motility of the medicament throughthe mucoadhesive polymeric diffusion environment to the mucosa.

Accordingly, in one embodiment, the present invention is directed tomethods for enhancing direct transmucosal delivery of a fentanyl orfentanyl derivative to a subject. The method generally includesadministering a bioerodable drug delivery device to an oral mucosalsurface of the subject, the device comprising: a fentanyl or fentanylderivative disposed in a mucoadhesive polymeric diffusion environment;and a barrier environment disposed relative to the polymeric diffusionenvironment such that a unidirectional gradient is created uponapplication to the mucosal surface and the fentanyl or fentanylderivative is delivered to the subject.

In another embodiment, the present invention is directed to methods fortreating pain in a subject. The method generally includes transmucosallyadministering to a subject a therapeutically effective amount of afentanyl or fentanyl derivative disposed in a mucoadhesive polymericdiffusion environment such that the effective amount of the fentanyl orfentanyl derivative is delivered in less than about 30 minutes. In someembodiments, chronic pain is alleviated in the subject. In otherembodiments, acute pain is alleviated in the subject. In otherembodiments, the pain is breakthrough cancer pain.

In yet another embodiment, the present invention is directed tomucoadhesive delivery devices suitable for direct transmucosaladministration of an effective amount of a fentanyl or fentanylderivative to a subject. The mucoadhesive device generally includes afentanyl or fentanyl derivative disposed in a polymeric diffusionenvironment; and a barrier environment disposed relative to thepolymeric diffusion environment such that a unidirectional gradient isupon application to a mucosal surface.

In another embodiment, the present invention is directed to transmucosaldelivery devices that deliver a fentanyl or fentanyl derivative with atleast 50% direct buccal absorption and an absolute bioavailability of atleast about 70%. In yet another embodiment, the present invention isdirected to transmucosal delivery devices that deliver a fentanyl orfentanyl derivative directly to the mucosa to achieve onset of painrelief (T_(first)) of about 0.20 hours or less and time to peak plasmaconcentration (T_(max)) of about 1.6 hours or more. In still anotherembodiment, the present invention is directed to devices comprisingabout 800 μg of fentanyl, which exhibit upon transmucosal administrationto a subject at least one in vivo plasma profile as follows: a C_(max)of about 1.10 ng/mL or more; a T_(first) of about 0.20 hours or less;and an AUC₀₋₂₄ of about 10.00 hr·ng/mL or more. In yet anotherembodiment, the present invention is directed to transmucosal deliverydevices which include a fentanyl or fentanyl derivative that deliversthe fentanyl or fentanyl derivative in an amount effective to treatpain, wherein oral irritation, oral ulceration and/or constipationassociated with the delivery of the fentanyl or fentanyl derivative isinsignificant or eliminated. In one embodiment, the pH of themucoadhesive polymeric diffusion environment is between about 6.5 andabout 8, e.g., about 7.25. In one embodiment, the device comprises about800 μg of fentanyl. In another embodiment, the device further comprisesat least one additional layer that facilitates unidirectional deliveryof the fentanyl or fentanyl derivative to the mucosa. In anotherembodiment, the fentanyl is fentanyl citrate.

In one embodiment, more than 30% of the fentanyl, e.g., more than 55% ofthe fentanyl, in the device becomes systemically available via mucosalabsorption.

In one embodiment, the present invention is directed to methods forenhancing direct transmucosal delivery of buprenorphine to a subject.The method generally includes administering a bioerodable drug deliverydevice to an oral mucosal surface of the subject, the device comprising:buprenorphine disposed in a mucoadhesive polymeric diffusionenvironment; and a barrier environment disposed relative to thepolymeric diffusion environment such that a unidirectional gradient iscreated upon application to the mucosal surface, and the buprenorphineis delivered to the subject.

In another embodiment, the present invention is directed to methods fortreating pain in a subject. The method generally includes transmucosallyadministering to a subject a therapeutically effective amount ofbuprenorphine disposed in a mucoadhesive polymeric diffusion environmentsuch that the effective amount of the buprenorphine is delivered in lessthan about 30 minutes. In some embodiments, chronic pain is alleviatedin the subject. In other embodiments, acute pain is alleviated in thesubject. In other embodiments, the pain is breakthrough cancer pain.

In yet another embodiment, the present invention is directed tomucoadhesive delivery devices suitable for direct transmucosaladministration of an effective amount of buprenorphine to a subject. Themucoadhesive device generally includes buprenorphine disposed in apolymeric diffusion environment; and a barrier environment disposedrelative to the polymeric diffusion environment such that aunidirectional gradient is created upon application to a mucosalsurface. In one embodiment, the pH is between about 4.0 and about 7.5,e.g., about 6.0 or about 7.25. In another embodiment, the device furthercomprises at least one additional layer that facilitates unidirectionaldelivery of the buprenorphine to the mucosa.

In one embodiment of the methods and devices of the present invention,the device comprises a pH buffering agent. In one embodiment of themethods and devices of the present invention, the device is adapted forbuccal administration or sublingual administration.

In one embodiment of the methods and devices of the present invention,the device is a mucoadhesive disc. In one embodiment of the methods anddevices of the present invention, the medicament is formulated as amucoadhesive film formed to delineate different dosages. In oneembodiment of the methods and devices of the present invention, thedevice comprises a backing layer disposed adjacent to the mucoadhesivepolymeric diffusion environment.

In one embodiment of the methods and devices of the present invention,the device further comprises an opioid antagonist. In one embodiment ofthe methods and devices of the present invention, the device furthercomprises naloxone.

In one embodiment of the methods and devices of the present invention,the device is a layered, flexible device. In one embodiment of themethods and devices of the present invention, the mucoadhesive polymericdiffusion environment has a buffered environment for the transmucosaladministration.

In one embodiment of the methods and devices of the present invention,there is substantially no irritation at the site of transmucosaladministration. In one embodiment of the methods and devices of thepresent invention, the subject experienced about a 50% decrease in painover about 30 minutes.

In one embodiment of the methods and devices of the present invention,the polymeric diffusion environment comprises at least one ionic polymersystem, e.g., polyacrylic acid (optionally crosslinked), sodiumcarboxymethylcellulose and mixtures thereof. In one embodiment, thepolymeric diffusion environment comprises a buffer system, e.g., citricacid, sodium benzoate or mixtures thereof. In some embodiments, thedevice has a thickness such that it exhibits minimal mouth feel. In someembodiments, the device has a thickness of about 0.25 mm.

In some embodiments, the present invention provides a flexible,bioerodable mucoadhesive delivery device suitable for directtransmucosal administration of an effective amount of a fentanyl,fentanyl derivative, buprenorphine or buprenorphine derivative to asubject. The mucoadhesive device includes a mucoadhesive layercomprising a fentanyl, fentanyl derivative, buprenorphine orbuprenorphine derivative disposed in a polymeric diffusion environment,wherein the polymeric diffusion environment has a pH of about 7.25 forthe fentanyl or fentanyl derivative or a pH of about 6 for thebuprenorphine or buprenorphine derivative; and a backing layercomprising a barrier environment which is disposed adjacent to andcoterminous with the mucoadhesive layer. The device has no or minimalmouth feel and is able to transmucosally deliver the effective amount ofthe, fentanyl derivative, buprenorphine or buprenorphine derivative inless than about 30 minutes; and wherein a unidirectional gradient iscreated upon application of the device to a mucosal surface.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other aspects, embodiments, objects, features andadvantages of the invention can be more fully understood from thefollowing description in conjunction with the accompanying figures.

FIGS. 1 and 2 are graphs comparing fentanyl citrate uptake in humansover 2 days post-administration, and 1 hour post-administration,respectively, for exemplary embodiments of the present invention and acommercially available delivery device (Actiq® Oral TransmucosalFentanyl Citrate) as described in Examples 1 and 2.

FIG. 3 is a graph comparing buprenorphine uptake in humans over 16 hourspost-administration, respectively, for exemplary embodiments of thepresent invention and a commercially available delivery devices asdescribed in Examples 3 and 4.

FIGS. 4A-C are schematic representations of exemplary embodiments of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based, at least in part, on the discovery thattransmucosal uptake of medicaments can be enhanced by employing a novelpolymeric diffusion environment. Such a polymeric diffusion environmentis advantageous, e.g., because the absolute bioavailability of themedicament contained therein is enhanced, while also providing a rapidonset. Additionally, less medicament is needed in the device to delivera therapeutic effect versus devices of the prior art. This renders thedevice less abusable, an important consideration when the medicament isa controlled substance, such as an opioid. The polymeric diffusionenvironment described in more detail herein, provides an enhanceddelivery profile and more efficient delivery of the medicament.Additional advantages of a polymeric diffusion environment are alsodescribed herein.

In order to more clearly and concisely describe the subject matter ofthe claims, the following definitions are intended to provide guidanceas to the meaning of terms used herein.

As used herein, the articles “a” and “an” mean “one or more” or “atleast one,” unless otherwise indicated. That is, reference to anyelement of the present invention by the indefinite article “a” or “an”does not exclude the possibility that more than one of the element ispresent.

As used herein, the term “acute pain” refers to pain characterized by ashort duration, e.g., three to six months. Acute pain is typicallyassociated with tissue damage, and manifests in ways that can be easilydescribed and observed. It can, for example, cause sweating or increasedheart rate. Acute pain can also increase over time, and/or occurintermittently.

As used herein, the term “chronic pain” refers to pain which persistsbeyond the usual recovery period for an injury or illness. Chronic paincan be constant or intermittent. Common causes of chronic pain include,but are not limited to, arthritis, cancer, Reflex Sympathetic DystrophySyndrome (RSDS), repetitive stress injuries, shingles, headaches,fibromyalgia, and diabetic neuropathy.

As used herein, the term “breakthrough pain” refers to paincharacterized by frequent and intense flares of moderate to severe painwhich occur over chronic pain, even when a subject is regularly takingpain medication. Characteristics of breakthrough pain generally include:a short time to peak severity (e.g., three to five minutes);excruciating severity; relatively short duration of pain (e.g., 15 to 30minutes); and frequent occurrence (e.g., one to five episodes a day).Breakthrough pain can occur unexpectedly with no obvious precipitatingevent, or it can be event precipitated. The occurrence of breakthroughpain is predictable about 50% to 60% of the time. Although commonlyfound in patients with cancer, breakthrough pain also occurs in patientswith lower back pain, neck and shoulder pain, moderate to severeosteoarthritis, and patients with severe migraine.

As used herein, unless indicated otherwise, the term “fentanyl”,includes any pharmaceutically acceptable form of fentanyl, including,but not limited to, salts, esters, and prodrugs thereof. The term“fentanyl” includes fentanyl citrate. As used herein, the term “fentanylderivative” refers to compounds having similar structure and function tofentanyl. In some embodiments, fentanyl derivatives include those of thefollowing formula:

or pharmaceutically acceptable salts or esters thereof, wherein

-   -   R₁ is selected from an aryl group, a heteroaryl group or a        COO—C₁₋₄ alkyl group; and R₂ is selected from —H, a —C₁₋₄        alkyl-O—C₁₋₄ alkyl group or a —COO—C₁₋₄ alkyl group.        Fentanyl derivatives include, but are not limited to,        alfentanil, sufentanil, remifentanil and carfentanil.

As used herein, unless indicated otherwise, the term “buprenorphine”,includes any pharmaceutically acceptable form of buprenorphine,including, but not limited to, salts, esters, and prodrugs thereof. Asused herein, the term “buprenorphine derivative” refers to compoundshaving similar structure and function to buprenorphine. In someembodiments, fentanyl derivatives include those of the followingformula:

-   -   or pharmaceutically acceptable salts or esters thereof, wherein

is a double or single bond; R₃ is selected from a —C₁₋₄ alkyl group or acycloalkyl-substituted-C₁₋₄ alkyl group; R₄ is selected from a —C₁₋₄alkyl; R₅ is —OH, or taken together, R₄ and R₅ form a ═O group; and R₆is selected from —H or a —C₁₋₄ alkyl group.Buprenorphine derivatives include, but are not limited to, etorphine anddiprenorphine.

As used herein, “polymeric diffusion environment” refers to anenvironment capable of allowing flux of a medicament to a mucosalsurface upon creation of a gradient by adhesion of the polymericdiffusion environment to a mucosal surface. The flux of a transportedmedicament is proportionally related to the diffusivity of theenvironment which can be manipulated by, e.g., the pH, taking intoaccount the ionic nature of the medicament and/or the ionic naturepolymer or polymers included in the environment and.

As used herein, “barrier environment” refers to an environment in theform of, e.g., a layer or coating, capable of slowing or stopping fluxof a medicament in its direction. In some embodiments, the barrierenvironment stops flux of a medicament, except in the direction of themucosa. In some embodiments, the barrier significantly slows flux of amedicament, e.g., enough so that little or no medicament is washed awayby saliva.

As used herein, the term “unidirectional gradient” refers to a gradientwhich allows for the flux of a medicament (e.g., fentanyl orbuprenorphine) through the device, e.g., through a polymeric diffusionenvironment, in substantially one direction, e.g., to the mucosa of asubject. For example, the polymeric diffusion environment may be amucoadhesive polymeric diffusion environment in the form of a layer orfilm disposed adjacent to a backing layer or film. Uponmucoadministration, a gradient is created between the mucoadhesivepolymeric diffusion environment and the mucosa, and the medicament flowsfrom the mucoadhesive polymeric diffusion environment, substantially inone direction towards the mucosa. In some embodiments, some flux of themedicament is not entirely unidirectional across the gradient; however,there is typically not free flux of the medicament in all directions.Such unidirectional flux is described in more detail herein, e.g., inrelation to FIG. 4.

As used herein, “treating” or “treatment” of a subject includes theadministration of a drug to a subject with the purpose of preventing,curing, healing, alleviating, relieving, altering, remedying,ameliorating, improving, stabilizing or affecting a disease or disorder,or a symptom of a disease or disorder (e.g., to alleviate pain).

The term “subject” refers to living organisms such as humans, dogs,cats, and other mammals. Administration of the medicaments included inthe devices of the present invention can be carried out at dosages andfor periods of time effective for treatment of a subject. In someembodiments, the subject is a human. In some embodiments, thepharmacokinetic profiles of the devices of the present invention aresimilar for male and female subjects. An “effective amount” of a drugnecessary to achieve a therapeutic effect may vary according to factorssuch as the age, sex, and weight of the subject. Dosage regimens can beadjusted to provide the optimum therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

The term “transmucosal,” as used herein, refers to any route ofadministration via a mucosal membrane. Examples include, but are notlimited to, buccal, sublingual, nasal, vaginal, and rectal. In oneembodiment, the administration is buccal. In one embodiment, theadministration is sublingual. As used herein, the term “directtransmucosal” refers to mucosal administration via the oral mucosa,e.g., buccal and/or sublingual.

As used herein, the term “water erodible” or “at least partially watererodible” refers to a substance that exhibits a water erodibilityranging from negligible to completely water erodible. The substance mayreadily dissolve in water or may only partially dissolve in water withdifficulty over a long period of time. Furthermore, the substance mayexhibit a differing erodibility in body fluids compared with waterbecause of the more complex nature of body fluids. For example, asubstance that is negligibly erodible in water may show an erodibilityin body fluids that is slight to moderate. However, in other instances,the erodibility in water and body fluid may be approximately the same.

The present invention provides transmucosal delivery devices thatuniformly and predictably deliver a medicament to a subject. The presentinvention also provides methods of delivery of a medicament to a subjectemploying devices in accordance with the present invention. Accordingly,in one embodiment, the present invention is directed to mucoadhesivedelivery devices suitable for direct transmucosal administration of aneffective amount of a medicament, e.g., fentanyl or fentanyl derivativeor buprenorphine to a subject. The mucoadhesive device generallyincludes a medicament disposed in a polymeric diffusion environment; anda having a barrier such that a unidirectional gradient is created uponapplication to a mucosal surface, wherein the device is capable ofdelivering in a unidirectional manner the medicament to the subject. Thepresent invention also provides methods of delivery of a medicament to asubject employing the devices in accordance with the present invention.

In another embodiment, the present invention is directed to methods forenhancing direct transmucosal delivery of a medicament, e.g., fentanyl,fentanyl derivatives and/or buprenorphine, to a subject. The methodgenerally includes administering a bioerodable drug delivery device toan oral mucosal surface of the subject, the device comprising: amedicament disposed in a mucoadhesive polymeric diffusion environment;and a barrier environment disposed relative to the polymeric diffusionenvironment such that a unidirectional gradient is created uponapplication to the mucosal surface, wherein an effective amount of themedicament is delivered to the subject.

In another embodiment, the present invention is directed to methods fortreating pain in a subject. The method generally includes transmucosallyadministering to a subject a therapeutically effective amount of amedicament, e.g., fentanyl, fentanyl derivatives and/or buprenorphine,disposed in a mucoadhesive polymeric diffusion environment having athickness such that the effective amount of the medicament is deliveredin less than about 30 minutes and such that pain is treated. In someembodiments, the medicament is delivered in less than about 25 minutes.In some embodiments, the medicament is delivered in less than about 20minutes.

In some embodiments of the above methods and devices, an effectiveamount is delivered transmucosally. In other embodiments, an effectiveamount is delivered transmucosally and by gastrointestinal absorption.In still other embodiments, an effective amount is deliveredtransmucosally, and delivery though the gastrointestinal absorptionaugments and/or maintains treatment, e.g., pain relief for a desiredperiod of time, e.g., at least 1, 1.5, 2, 2.5, 3, 3.5, or 4 or morehours.

In yet another embodiment, the present invention is directed totransmucosal delivery devices that deliver a fentanyl or fentanylderivative directly to the mucosa to achieve onset of pain relief(T_(first)) of about 0.20 hours or less and time to peak plasmaconcentration (T_(max)) of about 1.6 hours or more. The combination of arapid onset with a delayed maximum concentration is particularlyadvantageous when treating pain, e.g., relief for breakthrough cancerpain (BTP) in opioid tolerant patients with cancer, because immediaterelief is provided to alleviate a flare of moderate to severe pain butpersistence is also provided to alleviate subsequent flares.Conventional delivery systems may address either the immediate relief orsubsequent flare-ups, but the devices of this embodiment areadvantageous because they address both.

TABLE 1 Selected Pharmacokinetic properties of transmucosal devices.Total T_(first) T_(max) Bioavailability BEMA pH 7.25 0.15 hours 1.61hours 70% Actiq ® 0.23 hours 2.28 hours 47% Fentora ®  0.25 hours* 0.50hours 65% *reported as onset of main relief, first time point measured.

The devices of the present invention may have a number of additional oralternative desirable properties, as described in more detail herein.Accordingly, in another embodiment, the present invention is directed totransmucosal delivery devices that deliver a fentanyl or fentanylderivative with at least 50% direct buccal absorption and an absolutebioavailability of at least about 70%. In still another embodiment, thepresent invention is directed to devices comprising about 800 μg offentanyl, which exhibit upon transmucosal administration to a subject atleast one in vivo plasma profile as follows: a C_(max) of about 1.10ng/mL or more; a T_(first) of about 0.20 hours or less; and an AUC₀₋₂₄of about 10.00 hr·ng/mL or more.

The pain can be any pain known in the art, caused by any disease,disorder, condition and/or circumstance. In some embodiments, chronicpain is alleviated in the subject using the methods of the presentinvention. In other embodiments, acute pain is alleviated in the subjectusing the methods of the present invention. Chronic pain can arise frommany sources including, cancer, Reflex Sympathetic Dystrophy Syndrome(RSDS), and migraine. Acute pain is typically directly related to tissuedamage, and lasts for a relatively short amount of time, e.g., three tosix months. In other embodiments, the pain is breakthrough cancer pain.In some embodiments, the methods and devices of the present inventioncan be used to alleviate breakthrough pain in a subject. For example,the devices of the present invention can be used to treat breakthroughpain in a subject already on chronic opioid therapy. In someembodiments, the devices and methods of the present invention providerapid analgesia and/or avoid the first pass metabolism of fentanyl,thereby resulting in more rapid breakthrough pain relief than othertreatments, e.g., oral medications.

In one embodiment of the methods and devices of the present invention,the subject experienced about a 50% decrease in pain over about 30minutes. In one embodiment of the methods and devices of the presentinvention, the subject experienced about a 60% decrease in pain overabout 30 minutes. In one embodiment of the methods and devices of thepresent invention, the subject experienced about a 70% decrease in painover about 30 minutes. In one embodiment of the methods and devices ofthe present invention, the subject experienced about a 80% decrease inpain over about 30 minutes. In one embodiment of the methods and devicesof the present invention, the subject experienced about a 90% decreasein pain over about 30 minutes. In one embodiment of the methods anddevices of the present invention, the subject experienced about a 100%decrease in pain over about 30 minutes. In one embodiment of the methodsand devices of the present invention, the subject experienced about a50% decrease in pain over about 25 minutes. In one embodiment of themethods and devices of the present invention, the subject experiencedabout a 50% decrease in pain over about 20 minutes.

Without wishing to be bound by any particular theory, it is believedthat delivery of the medicament is particularly effective because themucoadhesive polymeric diffusion environment (e.g., the pH and the ionicnature of the polymers) is such that the medicament (e.g., a weaklybasic drug such as fentanyl or buprenorphine) can rapidly move throughthe mucoadhesive polymeric diffusion environment to the mucosa, whilealso allowing efficient absorption by the mucosa. For example, in someembodiments, the pH is low enough to allow movement of the medicament,while high enough for absorption.

In some embodiments, the mucoadhesive polymeric diffusion environment isa layer with a buffered pH such that a desired pH is maintained at themucosal administration site. Accordingly, the effect of any variation inpH encountered in a subject or between subjects (e.g., due to foods orbeverages recently consumed), including any effect on uptake, is reducedor eliminated.

Accordingly, one advantage of the present invention is that variabilityin the properties of the device (e.g., due to changes in the pH of theingredients) between devices, and from lot to lot is reduced oreliminated. Without wishing to be bound by any particular theory, it isbelieved that the polymeric diffusion environment of the presentinvention reduces variation, e.g., by maintaining a buffered pH. Yetanother advantage is pH variability at the administration site (e.g.,due to what food or drink or other medications was recently consumed) isreduced or eliminated, such that, e.g., the variability of the devicesis reduced or eliminated.

A medicament for use in the present invention includes any medicamentcapable of being administered transmucosally. The medicament can besuitable for local delivery to a particular mucosal membrane or region,such as the buccal and nasal cavities, throat, vagina, alimentary canalor the peritoneum. Alternatively, the medicament can be suitable forsystemic delivery via such mucosal membranes.

In one embodiment, the medicament can be an opioid. Opioids suitable foruse in the present invention include, e.g., alfentanil, allylprodine,alphaprodine, apomorphine, anileridine, apocodeine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,cyclorphan, cyprenorphine, desomorphine, dextromoramide,dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, eptazocine, ethylmorphine, etonitazene,etorphine, fentanyl, fencamfamine, fenethylline, hydrocodone,hydromorphone, hydroxymethylmorphinan, hydroxypethidine, isomethadone,levomethadone, levophenacylmorphan, levorphanol, lofentanil, mazindol,meperidine, metazocine, methadone, methylmorphine, modafinil, morphine,nalbuphene, necomorphine, normethadone, normorphine, opium, oxycodone,oxymorphone, pholcodine, profadol remifentanil, sufentanil, tramadol,corresponding derivatives, physiologically acceptable compounds, saltsand bases. In some embodiments, the medicament is fentanyl, e.g.,fentanyl citrate. In some embodiments, the medicament is buprenorphine.

The amount of medicament, e.g. fentanyl or buprenorphine, to beincorporated into the device of the present invention depends on thedesired treatment dosage to be administered, e.g., the fentanyl orfentanyl derivative can be present in about 0.001% to about 50% byweight of the device of the present invention, and in some embodimentsbetween about 0.005 and about 35% by weight or the buprenorphine can bepresent in about 0.001% to about 50% by weight of the device of thepresent invention, and in some embodiments between about 0.005 and about35% by weight. In one embodiment, the device comprises about 3.5% toabout 4.5% fentanyl or fentanyl derivative by weight. In one embodiment,the device comprises about 3.5% to about 4.5% buprenorphine by weight.In another embodiment, the device comprises about 800 μg of a fentanylsuch as fentanyl citrate. In another embodiment the device comprisesabout 25, 50, 75, 100, 150, 200, 300, 400, 500, 600, 700, 900, 1000,1200, 1500, 1600 or 2000 μg of a fentanyl such as fentanyl citrate orfentanyl derivative. It is to be understood that all values and rangesbetween these values and ranges are meant to be encompassed by thepresent invention. In another embodiment, the device comprises about 800μg of buprenorphine. In another embodiment the device comprises about100, 200, 300, 400, 500, 600, 700, 900, 1000, 1200, 1500, or 2000 μg ofbuprenorphine. In another embodiment the device comprises about 25, 50,75, 100, 150, 200, 300, 400, 500, 600, 700, 900, 1000, 1200, 1500, 1600or 2000 μg of any of the medicaments described herein.

One approach to reaching an effective dose is through titration withmultiple dosage units such that patients start with a single 200 mcgunit and progressively increase the number of units applied untilreaching an effective dose or 800 mcg (4 units) dose as the multiplediscs once an effective dose has been identified. Accordingly, in someembodiments, the methods of the present invention also include atitration phase to identify a dose that relieves pain and producesminimal toxicity, because the dose of opioid, e.g., fentanyl, requiredfor control of breakthrough pain episodes is often not easily predicted.The linear relationship between surface area of the devices of thepresent invention and pharmacokinetic profile may be exploited in thedose titration process through the application of single or multiplediscs to identify an appropriate dose, and then substitution of a singledisc containing the same amount of medicament.

In one embodiment, the devices of the present invention are capable ofdelivering a greater amount of fentanyl systemically to the subject thanconventional devices. According to the label for Actiq® OralTransmucosal Fentanyl Citrate, approximately 25% of the fentanyl in theACTIQ product is absorbed via the buccal mucosa, and of the remaining75% that is swallowed, another 25% of the total fentanyl becomesavailable via absorption in the GI tract for a total of 50% totalbioavailability. According to Fentora Fentanyl Buccal tablet literature,approximately 48% of the fentanyl in FENTORA product is absorbed via thebuccal mucosa, and of the remainig 52%, another 17% of the totalfentanyl becomes available via absorption in the GI tract for a total of65% total bioavailability. Accordingly, in some embodiments, more thanabout 30% of the fentanyl disposed in the devices of the presentinvention becomes systemically available or bioavailable via absorptionby the mucosa. In some embodiments, more than about 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75% or 80% becomes systemically available viamucosal absorption. In some embodiments, more than about 55%, 60%, 65%or 70% of the fentanyl disposed in the devices of the present inventionbecomes systemically available or bioavailable by any route, mucosaland/or GI tract. In some embodiments, more than about 60%, 65%, 70%,75%, 80%, 85%, 90%, or 95% becomes systemically available.

Accordingly, another advantage of the devices and methods of the presentinvention is that because the devices of the present invention moreefficiently deliver the medicament, e.g., fentanyl or buprenorphine,than do conventional devices, less medicament can be included than mustbe included in conventional devices to deliver the same amount ofmedicament. Accordingly, in some embodiments, the devices of the presentinvention are not irritating to the mucosal surface on which itattaches. In some embodiments, the devices of the present inventioncause little or no constipation, even when the devices include an opioidantagonist such as naloxone. In yet another embodiment, the presentinvention is directed to transmucosal delivery devices which include afentanyl or fentanyl derivative that delivers the fentanyl or fentanylderivative in an amount effective to treat pain, wherein oralirritation, oral ulceration and/or constipation associated with thedelivery of the fentanyl or fentanyl derivative is not significant oreliminated.

Another advantage is the devices of the present invention are lesssubject to abuse than conventional devices because less medicament,e.g., fentanyl or buprenorphine, is required in the device, i.e., thereis less medicament to be extracted by an abuser for injection into thebloodstream.

In some embodiments, the devices of the present invention have a doseresponse that is substantially directly proportional to the amount ofmedicament present in the device. For example, if the C_(max) is 10ng/mL for a 500 dose, then it is expected in some embodiments that a1000 μg dose will provide a C_(max) of approximately 20 ng/mL. Withoutwishing to be bound by any particular theory, it is believed that thisis advantageous in determining a proper dose in a subject.

In some embodiments, the devices of the present invention furthercomprise an opioid antagonist in any of various forms, e.g., as salts,bases, derivatives, or other corresponding physiologically acceptableforms. Opioid antagonists for use with the present invention include,but are not limited to, naloxone, naltrexone, nalmefene, nalide,nalmexone, nalorphine, naluphine, cyclazocine, levallorphan andphysiologically acceptable salts and solvates thereof, or combinationsthereof. In one embodiment, the device further comprises naloxone.

In some embodiments, the properties of the polymeric diffusionenvironment are effected by its pH. In one embodiment, e.g., when themedicament is fentanyl, the pH of the mucoadhesive polymeric diffusionenvironment in the devices of the present invention is between about 6.5and about 8. In another embodiment, the pH of the mucoadhesive polymericdiffusion environment is about 7.25. In another embodiment, the pH isbetween about 7.0 and about 7.5, or between about 7.25 and 7.5. In otherembodiments, the pH is about 6.5, 7.0, 7.5, 8.0 or 8.5, or anyincremental value thereof. It is to be understood that all values andranges between these values and ranges are meant to be encompassed bythe present invention.

In one embodiment, e.g., when the medicament is buprenorphine, the pH ofthe mucoadhesive polymeric diffusion environment in the devices of thepresent invention is between about 4.0 and about 7.5. In anotherembodiment, the pH of the mucoadhesive polymeric diffusion environmentis about 6.0. In one embodiment, the pH of the mucoadhesive polymericdiffusion environment is about 5.5 to about 6.5, or between about 6.0and 6.5. In yet another embodiment, the pH of the mucoadhesive polymericdiffusion environment is about 7.25. In another embodiment, the pH isbetween about 7.0 and 7.5, or between about 7.25 and 7.5. In otherembodiments, the pH of the device may be about 4.0, 4.5, 5.0, 5.5, 6.0,6.5, 7.0, or 7.5, or any incremental value thereof. It is to beunderstood that all values and ranges between these values and rangesare meant to be encompassed by the present invention.

The pH of the mucoadhesive polymeric diffusion environment can beadjusted and/or maintained by methods including, but not limited to, theuse of buffering agents, or by adjusting the composition of the deviceof the present invention. For example, adjustment of the components ofthe device of the present invention that influence pH, e.g., the amountof anti-oxidant, such as citric acid, contained in the device willadjust the pH of the device.

In some embodiments, the properties of the polymeric diffusionenvironment are effected by its buffering capacity. In some embodiments,buffering agents are included in the mucoadhesive mucoadhesive polymericdiffusion environment. Buffering agents suitable for use with thepresent invention include, for example, phosphates, such as sodiumphosphate; phosphates monobasic, such as sodium dihydrogen phosphate andpotassium dihydrogen phosphate; phosphates dibasic, such as disodiumhydrogen phosphate and dipotassium hydrogen phosphate; citrates, such assodium citrate (anhydrous or dehydrate); bicarbonates, such as sodiumbicarbonate and potassium bicarbonate may be used. In one embodiment, asingle buffering agent, e.g., a dibasic buffering agent is used. Inanother embodiment, a combination of buffering agents is employed, e.g.,a combination of a tri-basic buffering agent and a monobasic bufferingagent.

In one embodiment, the mucoadhesive polymeric diffusion environment ofthe device will have a buffered environment, i.e., a stabilized pH, forthe transmucosal administration of a medicament. The bufferedenvironment of the device allows for the optimal administration of themedicament to a subject. For example, the buffered environment canprovide a desired pH at the mucosa when in use, regardless of thecircumstances of the mucosa prior to administration.

Accordingly, in various embodiments, the devices include a mucoadhesivepolymeric diffusion environment having a buffered environment thatreduces or eliminates pH variability at the site of administration dueto, for example, medications, foods and/or beverages consumed by thesubject prior to or during administration. Thus, pH variationencountered at the site of administration in a subject from oneadministration to the next may have minimal or no effect on theabsorption of the medicament. Further, pH variation at theadministration site between different patients will have little or noeffect on the absorption of the medicament. Thus, the bufferedenvironment allows for reduced inter- and intra-subject variabilityduring transmucosal administration of the medicament. In anotherembodiment, the present invention is directed to methods for enhancinguptake of a medicament that include administering to a subject a deviceincluding a medicament disposed in a mucoadhesive polymeric diffusionenvironment having a buffered environment for the transmucosaladministration. In yet another embodiment, the present invention isdirected to methods of delivering a therapeutically effective amount ofa medicament to a subject that include administering a device includinga medicament disposed in a mucoadhesive polymeric diffusion environmenthaving a buffered environment for the transmucosal administration.

The devices of the present invention can include any combination orsub-combination of ingredients, layers and/or compositions of, e.g., thedevices described in U.S. Pat. No. 6,159,498, U.S. Pat. No. 5,800,832,U.S. Pat. No. 6,585,997, U.S. Pat. No. 6,200,604, U.S. Pat. No.6,759,059 and/or PCT Publication No. WO 05/06321. The entire contents ofthese patent and publications are incorporated herein by reference intheir entireties.

In some embodiments, the properties of the polymeric diffusionenvironment are effected by the ionic nature of the polymers employed inthe environment. In one embodiment, the mucoadhesive polymeric diffusionenvironment is water-erodible and can be made from a bioadhesivepolymer(s) and optionally, a first film-forming water-erodiblepolymer(s). In one embodiment, the polymeric diffusion environmentcomprises at least one ionic polymer system, e.g., polyacrylic acid(optionally crosslinked), sodium carboxymethylcellulose and mixturesthereof.

In some embodiments, the mucoadhesive polymeric diffusion environmentcan include at least one pharmacologically acceptable polymer capable ofbioadhesion (the “bioadhesive polymer”) and can optionally include atleast one first film-forming water-erodible polymer (the “film-formingpolymer”). Alternatively, the mucoadhesive polymeric diffusionenvironment can be formed of a single polymer that acts as both thebioadhesive polymer and the first film-forming polymer. Additionally oralternatively, the water-erodible mucoadhesive polymeric diffusionenvironment can include other first film-forming water-erodiblepolymer(s) and water-erodible plasticizer(s), such as glycerin and/orpolyethylene glycol (PEG).

In some embodiments, the bioadhesive polymer of the water-erodiblemucoadhesive polymeric diffusion environment can include any watererodible substituted cellulosic polymer or substituted olefinic polymerwherein the substituents may be ionic or hydrogen bonding, such ascarboxylic acid groups, hydroxyl alkyl groups, amine groups and amidegroups. For hydroxyl containing cellulosic polymers, a combination ofalkyl and hydroxyalkyl groups will be preferred for provision of thebioadhesive character and the ratio of these two groups will have aneffect upon water swellability and disperability. Examples includepolyacrylic acid (PAA), which can optionally be partially crosslinked,sodium carboxymethyl cellulose (NaCMC), moderately to highly substitutedhydroxypropylmethyl cellulose (HPMC), polyvinylpyrrolidone (PVP, whichcan optionally be partially crosslinked), moderately to highlysubstituted hydroxyethylmethyl cellulose (HEMC) or combinations thereof.In one embodiment, HEMC can be used as the bioadhesive polymer and thefirst film forming polymer as described above for a mucoadhesivepolymeric diffusion environment formed of one polymer. These bioadhesivepolymers are preferred because they have good and instantaneousmucoadhesive properties in a dry, system state.

The first film-forming water-erodible polymer(s) of the mucoadhesivepolymeric diffusion environment can be hydroxyalkyl cellulosederivatives and hydroxyalkyl alkyl cellulose derivatives preferablyhaving a ratio of hydroxyalkyl to alkyl groups that effectively promoteshydrogen bonding. Such first film-forming water-erodible polymer(s) caninclude hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropylmethyl cellulose (HPMC), hydroxyethylmethyl cellulose(HEMC), or a combination thereof. Preferably, the degree of substitutionof these cellulosic polymers will range from low to slightly abovemoderate.

Similar film-forming water-erodible polymer(s) can also be used. Thefilm-forming water-erodible polymer(s) can optionally be crosslinkedand/or plasticized in order to alter its dissolution kinetics.

In some embodiments, the mucoadhesive polymeric diffusion environment,e.g., a bioerodable mucoadhesive polymeric diffusion environment, isgenerally comprised of water-erodible polymers which include, but arenot limited to, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxyethylmethyl cellulose, polyacrylicacid (PAA) which may or may not be partially crosslinked, sodiumcarboxymethyl cellulose (NaCMC), and polyvinylpyrrolidone (PVP), orcombinations thereof. Other mucoadhesive water-erodible polymers mayalso be used in the present invention. The term “polyacrylic acid”includes both uncrosslinked and partially crosslinked forms, e.g.,polycarbophil.

In some embodiments, the mucoadhesive polymeric diffusion environment isa mucoadhesive layer, e.g, a bioerodable mucoadhesive layer. In someembodiments, the devices of the present invention include a bioerodablemucoadhesive layer which comprises a mucoadhesive polymeric diffusionenvironment.

In some embodiments, the properties of the polymeric diffusionenvironment are effected by the barrier environment. The barrierenvironment is disposed such that the flux of medicament issubstantially unidirectional. For example, in an exemplary layereddevice of the present invention, having a layer comprising a medicamentdispersed in a polymeric diffusion environment and a co-terminus barrierlayer (see, e.g., FIG. 4B), upon application to the mucosa, somemedicament may move to and even cross the boundary not limited by themucosa or barrier layer. In another exemplary layered device of thepresent invention, a barrier layer does not completely circumscribe theportion of the mucoadhesive polymeric diffusion environment that willnot be in direct contact with the mucosa upon application of the device(see, e.g., FIG. 4C). A majority of the medicament in both of thesecases, however, flows towards the mucosa. In another exemplary layereddevice of the present invention, having a barrier layer whichcircumscribes the portion of the mucoadhesive polymeric diffusionenvironment that will not be in direct contact with the mucosa uponapplication of the device (see, e.g., FIG. 4A), upon application to themucosa, substantially all of the medicament typically flows towards themucosa.

The barrier environment can be, e.g., a backing layer. A backing layercan be included as an additional layer disposed adjacent to themucoadhesive polymeric diffusion environment. The layers can becoterminous, or, e.g., the barrier layer may circumscribe the portion ofthe mucoadhesive polymeric diffusion environment that will not be indirect contact with the mucosa upon application of the device. In oneembodiment, the device comprises a backing layer disposed adjacent tothe mucoadhesive polymeric diffusion environment. The device of thepresent invention can also comprise a third layer or coating. A backinglayer can be also included in the devices of the present invention as alayer disposed adjacent to a layer which is, in turn, disposed adjacentto the mucoadhesive polymeric diffusion environment (i.e., a three layerdevice).

In one embodiment, the device further comprises at least one additionallayer that facilitates unidirectional delivery of the medicament to themucosa. In one embodiment, the device of the present invention furthercomprises at least one additional layer disposed adjacent to themucoadhesive polymeric diffusion environment. Such layer can includeadditional medicament or different medicaments, and/or can be present tofurther reduce the amount of medicament (originally in the mucoadhesivepolymeric diffusion environment) that is washed away in the saliva.

Specialty polymers and non-polymeric materials may also optionally beemployed to impart lubrication, additional dissolution protection, drugdelivery rate control, and other desired characteristics to the device.These third layer or coating materials can also include a component thatacts to adjust the kinetics of the erodability of the device.

The backing layer is a non-adhesive water-erodible layer that mayinclude at least one water-erodible, film-forming polymer. In someembodiments, the backing layer will at least partially or substantiallyerode or dissolve before the substantial erosion of the mucoadhesivepolymeric diffusion environment.

The barrier environment and/or backing layer can be employed in variousembodiments to promote unidirectional delivery of the medicament (e.g.,fentanyl) to the mucosa and/or to protect the mucoadhesive polymericdiffusion environment against significant erosion prior to delivery ofthe active to the mucosa. In some embodiments, dissolution or erosion ofthe water-erodible non-adhesive backing layer primarily controls theresidence time of the device of the present invention after applicationto the mucosa. In some embodiments, dissolution or erosion of thebarrier environment and/or backing layer primarily controls thedirectionality of medicament flow from the device of the presentinvention after application to the mucosa.

The barrier environment and/or backing layer (e.g., a water-erodiblenon-adhesive backing layer) can further include at least one watererodible, film-forming polymer. The polymer or polymers can includepolyethers and polyalcohols as well as hydrogen bonding cellulosicpolymers having either hydroxyalkyl group substitution or hydroxyalkylgroup and alkyl group substitution preferably with a moderate to highratio of hydroxyalkyl to alkyl group. Examples include, but are notlimited to, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropylmethyl cellulose (HPMC), hydroxyethylmethyl cellulose(HEMC), polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyethyleneoxide (PEO), ethylene oxide-propylene oxide co polymers, andcombinations thereof. The water-erodible non-adhesive backing layercomponent can optionally be crosslinked. In one embodiment, the watererodible non-adhesive backing layer includes hydroxyethyl cellulose andhydroxypropyl cellulose. The water-erodible non-adhesive backing layercan function as a slippery surface, to avoid sticking to mucous membranesurfaces.

In some embodiments, the barrier environment and/or backing layer, e.g.,a bioerodible non-adhesive backing layer, is generally comprised ofwater-erodible, film-forming pharmaceutically acceptable polymers whichinclude, but are not limited to, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, hydroxyethylmethyl cellulose,polyvinylalcohol, polyethylene glycol, polyethylene oxide, ethyleneoxide-propylene oxide co-polymers, or combinations thereof. The backinglayer may comprise other water-erodible, film-forming polymers.

The devices of the present invention can include ingredients that areemployed to, at least in part, provide a desired residence time. In someembodiments, this is a result of the selection of the appropriatebacking layer formulation, providing a slower rate of erosion of thebacking layer. Thus, the non-adhesive backing layer is further modifiedto render controlled erodibility which can be accomplished by coatingthe backing layer film with a more hydrophobic polymer selected from agroup of FDA approved Eudragit™ polymers, ethyl cellulose, celluloseacetate phthalate, and hydroxyl propyl methyl cellulose phthalate, thatare approved for use in other pharmaceutical dosage forms. Otherhydrophobic polymers may be used, alone or in combination with otherhydrophobic or hydrophilic polymers, provided that the layer derivedfrom these polymers or combination of polymers erodes in a moistenvironment. Dissolution characteristics may be adjusted to modify theresidence time and the release profile of a drug when included in thebacking layer.

In some embodiments, any of the layers in the devices of the presentinvention may also contain a plasticizing agent, such as propyleneglycol, polyethylene glycol, or glycerin in a small amount, 0 to 15% byweight, in order to improve the “flexibility” of this layer in the mouthand to adjust the erosion rate of the device. In addition, humectantssuch as hyaluronic acid, glycolic acid, and other alpha hydroxyl acidscan also be added to improve the “softness” and “feel” of the device.Finally, colors and opacifiers may be added to help distinguish theresulting non-adhesive backing layer from the mucoadhesive polymericdiffusion environment. Some opacifers include titanium dioxide, zincoxide, zirconium silicate, etc.

Combinations of different polymers or similar polymers with definitemolecular weight characteristics can be used in order to achievepreferred film forming capabilities, mechanical properties, and kineticsof dissolution. For example, polylactide, polyglycolide,lactide-glycolide copolymers, poly-e-caprolactone, polyorthoesters,polyanhydrides, ethyl cellulose, vinyl acetate, cellulose, acetate,polyisobutylene, or combinations thereof can be used.

The device can also optionally include a pharmaceutically acceptabledissolution-rate-modifying agent, a pharmaceutically acceptabledisintegration aid (e.g., polyethylene glycol, dextran, polycarbophil,carboxymethyl cellulose, or poloxamers), a pharmaceutically acceptableplasticizer, a pharmaceutically acceptable coloring agent (e.g., FD&CBlue #1), a pharmaceutically acceptable opacifier (e.g., titaniumdioxide), pharmaceutically acceptable anti-oxidant (e.g., tocopherolacetate), a pharmaceutically acceptable system forming enhancer (e.g.,polyvinyl alcohol or polyvinyl pyrrolidone), a pharmaceuticallyacceptable preservative, flavorants (e.g., saccharin and peppermint),neutralizing agents (e.g., sodium hydroxide), buffering agents (e.g.,monobasic, or tribasic sodium phosphate), or combinations thereof.Preferably, these components are individually present at no more thanabout 1% of the final weight of the device, but the amount may varydepending on the other components of the device.

The device can optionally include one or more plasticizers, to soften,increase the toughness, increase the flexibility, improve the moldingproperties, and/or otherwise modify the properties of the device.Plasticizers for use in the present invention can include, e.g., thoseplasticizers having a relatively low volatility such as glycerin,propylene glycol, sorbitol, ethylene glycol, diethylene glycol,triethylene glycol, propylene glycol, polypropylene glycol, dipropyleneglycol, butylene glycol, diglycerol, polyethylene glycol (e.g., lowmolecular weight PEG's), oleyl alcohol, cetyl alcohol, cetostearylalcohol, and other pharmaceutical-grade alcohols and diols havingboiling points above about 100° C. at standard atmospheric pressure.Additional plasticizers include, e.g., polysorbate 80, triethyl titrate,acetyl triethyl titrate, and tributyl titrate. Additional suitableplasticizers include, e.g., diethyl phthalate, butyl phthalyl butylglycolate, glycerin triacetin, and tributyrin. Additional suitableplasticizers include, e.g., pharmaceutical agent grade hydrocarbons suchas mineral oil (e.g., light mineral oil) and petrolatum. Furthersuitable plasticizers include, e.g., triglycerides such as medium-chaintriglyceride, soybean oil, safflower oil, peanut oil, and otherpharmaceutical agent grade triglycerides, PEGylated triglycerides suchas Labrifil®, Labrasol® and PEG-4 beeswax, lanolin, polyethylene oxide(PEO) and other polyethylene glycols, hydrophobic esters such as ethyloleate, isopropyl myristate, isopropyl palmitate, cetyl ester wax,glyceryl monolaurate, and glyceryl monostearate.

One or more disintegration aids can optionally be employed to increasethe disintegration rate and shorten the residence time of the device ofthe present invention. Disintegration aids useful in the presentinvention include, e.g., hydrophilic compounds such as water, methanol,ethanol, or low alkyl alcohols such as isopropyl alcohol, acetone,methyl ethyl acetone, alone or in combination. Specific disintegrationaids include those having less volatility such as glycerin, propyleneglycol, and polyethylene glycol.

One or more dissolution-rate-modifying agents can optionally be employedto decrease the disintegration rate and lengthen the residence time ofthe device of the present invention. Dissolution-rate modifying agentsuseful in the present invention include, e.g., hydrophobic compoundssuch as heptane, and dichloroethane, polyalkyl esters of di andtricarboxylic acids such as succinic and citric acid esterified with C6to C20 alcohols, aromatic esters such as benzyl benzoate, triacetin,propylene carbonate and other hydrophobic compounds that have similarproperties. These compounds can be used alone or in combination in thedevice of the invention.

The devices of the present invention can include various forms. Forexample, the device can be a disc or film. In one embodiment, the devicecomprises a mucoadhesive disc. In one embodiment of the methods anddevices of the present invention, the device is a layered, flexibledevice. The thickness of the device of the present invention, in itsform as a solid film or disc, may vary, depending on the thickness ofeach of the layers. Typically, the bilayer thickness ranges from about0.01 mm to about 1 mm, and more specifically, from about 0.05 mm toabout 0.5 mm. The thickness of each layer can vary from about 10% toabout 90% of the overall thickness of the device, and specifically canvary from about 30% to about 60% of the overall thickness of the device.Thus, the preferred thickness of each layer can vary from about 0.005 mmto about 1.0 mm, and more specifically from about 0.01 mm to about 0.5mm.

In one embodiment, the mucoadhesive polymeric diffusion environment ofthe device of the present invention has a thickness of about 0.03 mm toabout 0.07 mm. In one embodiment, the mucoadhesive polymeric diffusionenvironment of the device of the present invention has a thickness ofabout 0.04 mm to about 0.06 mm. In yet another embodiment, themucoadhesive polymeric diffusion environment of the present inventionhas a thickness of about 0.05 mm. The thickness of the mucoadhesivepolymeric diffusion environment is designed to be thick enough so thatit can be easily manufactured, yet thin enough to allow for maximumpermeability of the medicament through the layer, and maximum absorptionof the medicament into the mucosal layer.

In one embodiment, the backing layer of the device of the presentinvention has a thickness of about 0.050 mm to about 0.350 mm. In oneembodiment, the backing layer of the device of the present invention hasa thickness of about 0.100 mm to about 0.300 mm. In yet anotherembodiment, the backing layer of the present invention has a thicknessof about 0.200 mm. The thickness of the backing layer is designed to bethick enough so that it allows for substantially unidirectional deliveryof the medicament (towards the mucosa), yet thin enough to dissolve sothat it does not have to be manually removed by the subject.

In these embodiments, there is relatively minimal mouth feel and littlediscomfort because of the thinness and flexibility of the devices ascompared to conventional tablet or lozenge devices. This is especiallyadvantageous for patients who have inflammation of the mucosa and/or whomay otherwise not be able to comfortably use conventional devices. Thedevices of the present invention are small and flexible enough so thatthey can adhere to a non-inflamed area of the mucosa and still beeffective, i.e., the mucosa does not need to be swabbed with the deviceof the present invention.

In various embodiments, the devices of the present invention can be inany form or shape such as a sheet or disc, circular or square in profileor cross-section, etc., provided the form allows for the delivery of theactive to the subject. In some embodiments, the devices of the presentinvention can be scored, perforated or otherwise marked to delineatecertain dosages. For example, a device may be a square sheet, perforatedinto quarters, where each quarter comprises a 200 μg dose. Accordingly,a subject can use the entire device for an 800 μg dose, or detach anyportion thereof for a 200 μg, 400 μg or 600 μg dose.

The devices of the present invention can be adapted for any mucosaladministration. In some embodiments of the methods and devices of thepresent invention, the device is adapted for buccal administrationand/or sublingual administration.

Yet another advantage of the devices of the present invention is theease with which they are administered. With conventional devices, theuser must hold the device in place, or rub the device over the mucosafor the duration of administration, which may last from twenty to thirtyminutes or more. The devices of the present invention adhere to themucosal surface in less than about five seconds, and naturally erode inabout twenty to thirty minutes, without any need to hold the device inplace.

Without wishing to be bound by any particular theory, it is alsobelieved that the devices of the present invention are substantiallyeasier to use than devices of the prior art. When devices of the priorart are used, they are often subject to much variability, e.g., due tovariation in mouth size, diligence of the subject in correctlyadministering the device and amount of saliva produced in the subject'smouth. Accordingly, in some embodiments, the present invention providesa variable-free method for treating pain in a subject. The term“variable-free” as used herein, refers to the fact that the devices ofthe present invention provide substantially similar pharmacokineticprofile in all subjects, regardless of mouth size and saliva production.

Without wishing to be bound by any particular theory, it is alsobelieved that the presence of a backing layer also imparts a resistanceto the devices of the present invention. Accordingly, in someembodiments, the devices of the present invention are resistant to theconsumption of food or beverage. That is, the consumption of food orbeverage while using the devices of the present invention does notsubstantially interfere with the effectiveness of the device. In someembodiments, the performance of the devices of the present invention,e.g., peak fentanyl concentrations and/or overall exposure to themedicament is unaffected by the consumption of foods and/or hotbeverages.

In various embodiments, the devices can have any combination of thelayers, ingredients or compositions described herein including but notlimited to those described above.

EXEMPLIFICATION Example 1 Preparation of Devices in Accordance with thePresent Invention

Transmucosal devices were configured in the form of a disc, rectangularin shape with round corners, pink on one side and white on the otherside. The drug is present in the pink layer, which is the mucoadhesivepolymeric diffusion environment, and this side is to be placed incontact with the buccal mucosa (inside the cheek). The drug is deliveredinto the mucosa as the disc erodes in the mouth. The white side is thenon-adhesive, backing layer which provides a controlled erosion of thedisc, and minimizes the oral uptake of the drug induced by constantswallowing, thus minimizing or preventing first pass metabolism. Themucoadhesive polymeric diffusion environment and backing layer arebonded together and do not delaminate during or after application.

The backing layer was prepared by adding water (about 77% totalformulation, by weight) to a mixing vessel followed by sequentialaddition of sodium benzoate (about 0.1% total formulation, by weight),methylparaben (about 0.1% total formulation, by weight) andpropylparaben (about 0.03% total formulation, by weight), citric acid(about 0.1% total formulation, by weight) and vitamin E acetate (about0.01% total formulation, by weight), and sodium saccharin (about 0.1%total formulation, by weight). Subsequently, a mixture of the polymershydroxypropyl cellulose (Klucel EF, about 14% total formulation, byweight) and hydroxyethyl cellulose (Natrosol 250L, about 7% totalformulation, by weight) was added and stirred at a temperature betweenabout 120 and 130° F., until evenly dispersed. Upon cooling to roomtemperature, titanium dioxide (about 0.6% total formulation, by weight)and peppermint oil (about 0.2% total formulation, by weight) were thenadded to the vessel and stirred. The prepared mixture was stored in anair-sealed vessel until it was ready for use in the coating operation.

The mucoadhesive polymeric diffusion environment was prepared by addingwater (about 89% total formulation, by weight) to a mixing vesselfollowed by sequential addition of propylene glycol (about 0.5% totalformulation, by weight), sodium benzoate (about 0.06% total formulation,by weight), methylparaben (about 0.1% total formulation, by weight) andpropylparaben (about 0.03% total formulation, by weight), vitamin Eacetate (about 0.01% total formulation, by weight) and citric acid(about 0.06% total formulation, by weight), red iron oxide (about 0.01%total formulation, by weight), and monobasic sodium phosphate (about0.04% total formulation, by weight). After the components weredissolved, 800 μg fentanyl citrate (about 0.9% total formulation, byweight) was added, and the vessel was heated to 120 to 130° F. Afterdissolution, the polymer mixture [hydroxypropyl cellulose (Klucel EF,about 0.6% total formulation, by weight), hydroxyethyl cellulose(Natrosol 250L, about 1.9% total formulation, by weight), polycarbophil(Noveon AA1(about 0.6% total formulation, by weight), and carboxy methylcellulose (Aqualon 7LF, about 5.124% total formulation, by weight)] wasadded to the vessel, and stirred until dispersed. Subsequently, heat wasremoved from the mixing vessel. As the last addition step, tribasicsodium phosphate and sodium hydroxide were added to adjust the blend toa desired pH. For example, about 0.6% total formulation, by weight ofsodium hydroxide and about 0.4% total formulation, by weight of tribasicsodium phosphate can be added to the formulation. Batches were madehaving pHs of about 6, 7.25, and 8.5. The blend was mixed under vacuumfor a few hours. Each prepared mixture was stored in an air-sealedvessel until its use in the coating operation.

The layers were cast in series onto a St. Gobain polyester liner. First,the backing layer was cast using a knife-on-a-blade coating method. Thebacking layer was then cured in a continuous oven at about 65 to 95° C.and dried. After two coating and drying iterations, an approximately 8mil (203 to 213 micrometers) thick backing layer is obtained.Subsequently, the mucoadhesive polymeric diffusion environment was castonto the backing layer, cured in an oven at about 65 to 95° C. anddried. The devices were then die-cut by kiss-cut method and removed fromthe casting surface.

Example 2 Study of Fentanyl Citrate Uptake in Humans for DeliveryDevices of the Present Invention and a Commercially Available DeliveryDevice

The effect of system pH on the uptake of fentanyl citrate in threeexemplary delivery devices of the present invention was evaluated, andcompared to that observed in Actiq® Oral Transmucosal Fentanyl Citrateproduct (Cephalon, Inc., Salt Lake City, Utah), referred to herein as“OTFC”. A randomized, open-label, single-dose, four-period, Latin-squarecrossover study was conducted in 12 healthy volunteers. An EthicalReview Board approved the study and all subjects gave informed consentbefore participating. Bioanalytical work using a validated liquidchromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method wasperformed by CEDRA Clinical Research, LLC (Austin, Tex.).

Twelve (9 male, 3 female) healthy volunteers ranging in age from 21 to44 years were recruited for the instant study. Subjects tested were freefrom any significant clinical abnormalities on the basis of medicalhistory and physical examination, electrocardiogram, and screeninglaboratories. Subjects weighed between about 50 kg and 100 kg and werewithin 15% of their ideal body weight based on Metropolitan Life tablesfor height and weight. Subjects were instructed to not consume alcohol,caffeine, xanthine, or foods/beverages containing grapefruit for 48hours prior to the first dose of study medication and for the entireduration of the study. Subjects were also instructed not to use tobaccoor nicotine containing products for at least 30 days prior to the firstdose of medication. No subject had participated in any investigationaldrug study for at least 30 days prior to the instant study; had anysignificant medical condition either at the time of the study or in thepast (including glaucoma and seizure disorders); had a positive drugscreen; had used any concomitant medication other than oralcontraceptives or acetaminophen for at least 72 hours prior to the firstdose; or had a history of allergic reaction or intolerance to narcotics.Premenopausal women not using contraception or having a positive urinebeta HCG test were excluded. Table 2, below, shows the demographics ofthe subjects included in this study.

Table 2. Subject Demographics (N=12)

TABLE 2 Subject Demographics (N = 12) Age, years Mean (standarddeviation)   32 (7) Median  31 Range   21-44 Gender, n (%) Female    3(25) Male    9 (75) Race, n (%) Black    3 (25) Caucasian    4 (33)Hispanic    5 (42) Height (cm) Mean (standard deviation) 171.6 (9.3)Median 172.0 Range 155.0-183.5 Weight (kg) Mean (standard deviation) 70.5 (9.0) Median  70.7 Range  52.0-86.5

The study consisted of a screening visit and a 9-day inpatient periodduring which each subject received single buccal transmucosal doses ofeach of the four study treatments with 48 hours separating the doses.The four study treatments, each including 800 μg of fentanyl citrate,were: the OTFC and devices prepared as described in Example 1 andbuffered at a pH of about 6 (“device at pH 6”), a pH of about 7.25(“device at pH 7.25”), and a pH of about 8.5 (“device at pH 8.5”).

Subject eligibility was determined at the screening visit, up to 21 daysprior to entering the study facility. Subjects arrived at the studyfacility at 6:00 PM the day prior to dosing (day 0). Predose procedures(physical examination, clinical laboratory tests, electrocardiogram, andsubstance abuse screen) were performed. After an overnight fast of atleast 8 hours, subjects received an oral dose of naltrexone at 6 AM. Astandard light breakfast was served approximately 1 hour prior to studydrug dosing. A venous catheter was placed in a large forearm or handvein for blood sampling, and a pulse oximeter and noninvasive bloodpressure cuff were attached. Subjects were placed in a semi-recumbentposition, which they maintained for 8 hours after each dose.

Subjects received the first dose of drug at 8 AM on day 1 and subsequentdoses at the same time on days 3, 5, and 7. Blood samples (7 mL) werecollected in ethylenediaminetetraacetic acid (EDTA) for measurement ofplasma fentanyl just prior to dose 1 and 5, 7.5, 10, 15, 20, 25, 30, 45,and 60 minutes, and 2, 3, 4, 8, 12, 16, 20, 24, and 48 hours after eachdose. The 48-hour post dose sample was collected just prior toadministration of the subsequent dose. A total of 511 mL of blood wascollected over the study period for pharmacokinetic analysis. Sampleswere centrifuged and the plasma portion drawn off and frozen at −20° C.or colder.

Finger pulse oximetry was monitored continuously for 8 hours after eachdose and then hourly for an additional four hours. If the subject'soxyhemoglobin saturation persistently decreased to less than 90%, thesubject was prompted to inhale deeply several times and was observed forsigns of decreased oxyhemoglobin saturation. If the oxyhemoglobinsaturation value immediately increased to 90% or above, no furtheraction was taken. If the oxyhemoglobin saturation remained below 90% formore than 1 minute, oxygen was administered to the subject via a nasalcannula. Heart rate, respiratory rate, and blood pressure were measuredjust prior to the dose, and every 15 minutes for 120 minutes, and at 4,6, 8, and 12 hours post dose. Throughout the study, subjects wereinstructed to inform the study personnel of any adverse events.

Each subject received a single buccal dose of each of the 4 studytreatments in an open-label, randomized crossover design. The measuredpH on the three devices during the manufacturing process in accordancewith Example 1 were 5.95 for the device at pH 6.0, 7.44 for the deviceat pH 7.25, and 8.46 for the device at pH 8.5. After subjects rinsedtheir mouths with water, the delivery devices of the present inventionwere applied to the oral mucosa at a location approximately even withthe lower teeth. The devices were held in place for 5 seconds until thedevice was moistened by saliva and adhered to the mucosa membrane. Afterapplication, subjects were instructed to avoid rubbing the device withtheir tongues, as this would accelerate the dissolution of the device.

OTFC doses were administered according to the package insert. After eachmouth was rinsed with water, the OTFC unit was placed in the mouthbetween the cheek and lower gum. The OTFC unit was occasionally movedfrom one side of the mouth to the other. Subjects were instructed tosuck, not chew, the OTFC unit over a 15-minute period. To block therespiratory depressive effects of fentanyl, a 50 mg oral dose ofnaltrexone was administered to each subject at approximately 12 hoursand 0.5 hours prior to each dose of study drug and 12 hours after studydrug. Naltrexone has been shown not to interfere with fentanylpharmacokinetics in opioid naïve subjects. Lor M, et al., Clin PharmacolTher; 77: P76 (2005).

At the end of the study, EDTA plasma samples were analyzed for plasmafentanyl concentrations using a validated liquid chromatography withtandem mass spectrophotometry (LC/MS/MS) procedure. Samples wereanalyzed on a SCIEX API 3000 spectrophotometer using pentadeuteratedfentanyl as an internal standard. The method was validated for a rangeof 0.0250 to 5.00 ng/mL based on the analysis of 0.500 mL of EDTA humanplasma. Quantitation was performed using a weighted (1/X2) linear leastsquares regression analysis generated from calibration standards.

Pharmacokinetic data were analyzed by noncompartmental methods inWinNonlin (Pharsight Corporation). In the pharmacokinetic analysis,concentrations below the limit of quantitation (<0.0250 ng/mL) weretreated as zero from time-zero up to the time at which the firstquantifiable concentration (C_(first)) was observed. Subsequent toC_(first), concentrations below this limit were treated as missing. Fullprecision concentration data were used for all pharmacokinetic andstatistical analyses. C_(first) was defined as the first quantifiableconcentration above the pre-dose concentration because quantifiable datawere observed in the pre-dose samples in some subjects. λ_(z) wascalculated using unweighted linear regression analysis on at least threelog-transformed concentrations visually assessed to be on the linearportion of the terminal slope. The t_(1/2) was calculated as the ratioof 0.693 to λ_(z). Pharmacokinetic parameters were summarized bytreatment using descriptive statistics. Values of t_(first), t_(max),C_(max), and AUC_(inf) of the three exemplary devices of the presentinvention were compared to OTFC using an analysis of variance (ANOVA)model and Tukey's multiple comparison test. Statistical analysis wasperformed using SAS (SAS Institute Inc.). Table 3, below, presents thefentanyl pharmacokinetics for all 4 treatments after a single dose.

TABLE 3 Pharmacokinetic Parameters of OTFC and Three Formulations ofBEMA Fentanyl Citrate Device at pH 6 Device at pH 7.25 Device at pH 8.5OTFC 800 μg Fentanyl 800 μg Fentanyl 800 μg Fentanyl 800 μg (N = 12) (N= 12) (N = 12) (N = 12) Mean CV Mean CV Mean CV Mean CV Parameter (SD) %(SD) % (SD) % (SD) % t_(first) (hr) 0.23 78.03 0.13 27.99 0.15 54.180.21 55.21 (0.18) (0.04) (0.08) (0.11) C_(first) 0.07 64.95 0.05 35.250.06 41.59 0.06 30.08 (ng/mL) (0.05) (0.02) (0.02) (0.02) t_(max) (hr)2.28 58.04 2.15 53.23 1.61 64.49 2.21 60.64 (1.32) (1.14) (1.04) (1.34)C_(max) 1.03 24.19 1.40 35.12 1.67 45.07 1.39 29.44 (ng/mL)¹ (0.25)(0.49) (0.75) (0.41) AUC_(last) 9.04 39.01 12.17 35.19 12.98 43.04 11.8238.37 (hr · ng/mL) (3.53) (4.28) (5.59) (4.54) AUC₀₋₂₄ 7.75 32.48 10.4328.74 11.38 37.78 10.18 31.44 (hr · ng/mL) (2.52) (3.00) (4.30) (3.20)AUC_(inf) 10.30 37.29 13.68 33.24 14.44 37.33 13.11 36.40 (hr · ng/mL)(3.84) (4.55) (5.39) (4.77) % AUC_(extrap) 12.15 68.40 11.53 59.33 11.7258.96 10.31 43.49 (8.31) (6.84) (6.91) (4.49) λz (hr⁻¹) 0.05 37.83 0.0531.10 0.05 21.18 0.06 26.98 (0.02) (0.02) (0.01) (0.02) t_(1/2) (hr)15.33 44.67 15.12 33.66 14.28 19.23 13.33 31.04 (6.85) (5.09) (2.75)(4.14) MRT 15.92 38.73 15.73 26.63 14.45 21.61 14.31 31.09 (6.17) (4.19)(3.12) (4.45) ¹Mean differences of BEMA fentanyl formulations and OTFCsignificantly different by ANOVA, p = 0.0304.

Abbreviations used herein are as follows: C_(first) is the firstquantifiable drug concentration in plasma determined directly fromindividual concentration-time data; t_(first) is the time to the firstquantifiable concentration; C_(max) is the maximum drug concentration inplasma determined directly from individual concentration-time data;t_(max) is the time to reach maximum concentration; λ_(z) is theobserved elimination rate constant; t_(1/2) is the observed terminalelimination half-life calculated as ln(2)/λ_(z); AUC₀₋₂₄ is the areaunder the concentration-time curve from time zero to 24 hours post-dose;calculated using the linear trapezoidal rule and extrapolated using theelimination rate constant if quantifiable data were not observed through24 hours; AUC_(last) is the area under the concentration-time curve fromtime zero to the time of the last quantifiable concentration; calculatedusing the linear trapezoidal rule; AUC_(inf) is the area under theconcentration-time curve from time zero extrapolated to infinity,calculated as AUC_(last)+C_(last)/λ_(z); AUC_(extrap) (%) is thepercentage of AUC_(inf) based on extrapolation; MRT is the meanresidence time, calculated as AUMC_(inf)/AUC_(inf), where AUMC_(inf) isthe area under the first moment curve (concentration-time vs. time),calculated using the linear trapezoidal rule form time zero to T_(last)(AUMC_(last)) and extrapolated to infinity. It should be noted that,because quantifiable data were observed in the pre-dose samples for somesubjects, C_(first) was redefined as the first quantifiableconcentration above the pre-dose concentration, which was set to zero incalculating mean fentanyl concentrations.

FIG. 1 illustrates the plasma fentanyl concentration from 0 to 48 hourspost-dose for the OTFC dose and the doses provided by the threeexemplary devices of the present invention. The device at pH 7.25provided the highest peak concentrations of fentanyl of the threedevices of the present invention used in this study. In general, OTFCprovided lower fentanyl concentrations for most time points as comparedwith the devices of the present invention. The device at pH 6 and thedevice at pH 8.5 yielded very similar concentration-time profiles, withC_(max) values of 1.40 ng/mL and 1.39 ng/mL, respectively. These valuesare midway between the maximum plasma fentanyl values of 1.03 ng/mL forOTFC and 1.67 ng/mL for the device at pH 7.25. After approximately 6hours post-dose, the fentanyl concentration-time profiles for the threedevices of the present invention were similar. The differences infentanyl C_(max) values were statistically significant when comparingall of the devices of the present invention to OTFC (p=0.0304), and forpairwise comparisons of the device at pH 7.25 to OTFC (p<0.05).

In general, quantifiable fentanyl concentrations were observed earlierafter administration of one of the three exemplary devices of thepresent invention (mean t_(first) of 8 to 13 minutes) compared with OTFC(mean t_(first) of 14 minutes). The device at pH 7.25 yielded theearliest average t_(max) (1.61 hours) and highest C_(max) (mean 1.67ng/mL). As shown in FIG. 2, fentanyl absorption from a device at pH 7.25was more rapid over the first hour post dose than from OTFC, with30-minute mean plasma concentrations of 0.9 ng/mL for the device at pH7.25 and 0.5 ng/mL for OTFC.

The delivery devices of the present invention provided overall greaterexposure to fentanyl, based on AUC₀ ₂₄ as compared to OTFC. Fentanylexposure as measured by AUC₀₋₂₄ values, were similar across groupstreated with one of the devices of the present invention, suggestingthat comparable amounts of fentanyl enter the systemic circulation fromeach of the devices. The device at pH 7.25, however, demonstratedapproximately 19% greater maximum plasma fentanyl concentration.

Overall, fentanyl concentrations were observed earlier and increasedmore rapidly after administration of a device of the present inventioncompared with OTFC. Mean 30 and 60 minute plasma fentanyl concentrationsobserved with use of the device at pH 7.25 were 1.8 and 1.7 times higherthan with OTFC, respectively. Similarly, the maximum plasma fentanylconcentration was 60% higher using a device of the present invention(mean 1.67 ng/mL) when compared to use of OTFC (mean 1.03 ng/mL). TheC_(max) for OTFC identified in this study is nearly identical to the 1.1ng/mL C_(max) value reported by Lee and co-workers with both a single800 mcg lozenge as well as two 400 mcg lozenges. Lee, M., et al., J PainSymptom Manage 2003; 26:743-747. Overall, fentanyl exposure for thefentanyl formulations of the present invention were greater than forOTFC. Mean estimates of AUC_(last) and AUC_(inf) were slightly larger,but the same general trends were observed. This indicates that thetransmucosal uptake is significantly improved in the devices of thepresent invention as compared to OTFC.

Mean t_(1/2) values and MRT values were similar for all treatment groupsand the values in both cases followed the same trend. Additionally,because MRT after extravascular administration is dependent on theabsorption and elimination rates, the MRT values suggest that fentanylabsorbs faster from a delivery device of the present invention,particularly with the device at pH 7.25 and the device at pH 8.5. Thisobservation is consistent with the t_(max) for the delivery devices ofthe present invention relative to OTFC.

Adverse events were similar across treatment groups and confounded bythe co-administration of naltrexone with each study treatment. The mostfrequent adverse events were sedation and dizziness. One subjectexperienced oral mucosal irritation with OTFC. No subject experiencedmucosal irritation with any of the three exemplary devices of thepresent invention. All reported adverse events were mild or moderate innature.

As demonstrated above, the delivery devices of the present inventionprovide significantly higher plasma fentanyl concentrations than OTFC.The delivery device at pH 7.25 appeared to provide enhanced uptakebelieved to be attributable to a favorable balance between drugsolubility and ionization. Similar studies have shown that the deliverydevices of the present invention provide an absolute bioavailability ofabout 70.5% and buccal absorption was about 51% (estimated bysubtracting the AUC_(inf) following an oral dose of fentanyl from theAUC_(inf) following BEMA fentanyl applied to the buccal mucosa, dividingby the single disc BEMA Fentanyl AUC_(inf), and multiplying by 100).

Example 3 Preparation of Devices in Accordance with the PresentInvention

Devices containing buprenorphine were also produced using the samemethod as described in Example 1, except that buprenorphine was added tothe mucoadhesive polymeric diffusion environment, rather than fentanylcitrate.

Example 4 Study of Buprenorphine Uptake in Humans for Delivery Devicesof the Present Invention

A study similar to that described in Example 2 was also performed withbuprenorphine in exemplary devices of the present invention (at pH 6 and7.25), suboxone sublingual and buprenex intramuscular. Results from thisstudy are summarized in the graph in FIG. 3. As demonstrated in Table 4,the delivery devices of the present invention at pH 6 appeared toprovide enhanced uptake believed to be attributable to a favorablebalance between drug solubility and ionization.

TABLE 4 Pharmacokinetic data for buprenorphine pH 6 7.25 t_(first) (hr)0.75 0.75 C_(first) (ng/mL) 0.0521 0.0845 t_(max) (hr) 3 3 C_(max)(ng/mL)¹ 1.05 0.86

EQUIVALENTS

Numerous modifications and alternative embodiments of the presentinvention will be apparent to those skilled in the art in view of theforegoing description. Accordingly, this description is to be construedas illustrative only and is for the purpose of teaching those skilled inthe art the best mode for carrying out the present invention. Details ofthe structure may vary substantially without departing from the spiritof the invention, and exclusive use of all modifications that comewithin the scope of the appended claims is reserved. It is intended thatthe present invention be limited only to the extent required by theappended claims and the applicable rules of law.

All literature and similar material cited in this application,including, patents, patent applications, articles, books, treatises,dissertations and web pages, regardless of the format of such literatureand similar materials, are expressly incorporated by reference in theirentirety. In the event that one or more of the incorporated literatureand similar materials differs from or contradicts this application,including defined terms, term usage, described techniques, or the like,this application controls.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described inany way.

While the present inventions have been described in conjunction withvarious embodiments and examples, it is not intended that the presentteachings be limited to such embodiments or examples. On the contrary,the present inventions encompass various alternatives, modifications,and equivalents, as will be appreciated by those of skill in the art.

The claims should not be read as limited to the described order orelements unless stated to that effect. It should be understood thatvarious changes in form and detail may be made without departing fromthe scope of the appended claims. Therefore, all embodiments that comewithin the scope and spirit of the following claims and equivalentsthereto are claimed.

1. A method for delivering buprenorphine to a subject comprising:administering a mucoadhesive biodegradable drug delivery device fortransmucosal delivery, the device comprising: a bioerodible mucoadhesivelayer comprising buprenorphine disposed in a polymeric diffusionenvironment, wherein the polymeric diffusion environment has a pH ofbetween about 4 and about 7.5, and a polymeric barrier environmentdisposed adjacent to the mucoadhesive layer, and wherein aunidirectional diffusion gradient of buprenorphine is provided uponapplication to a buccal surface.
 2. The method of claim 1, wherein thepolymeric diffusion environment comprises at least one film-formingwater-erodible adhesive polymer and at least one bioadhesive polymer. 3.The method of claim 1, wherein said polymeric barrier environmentcomprises at least one film-forming water-erodible polymer.
 4. Themethod of claim 1, wherein the polymeric diffusion environment has a pHof between about 4 to about
 6. 5. The method of claim 1, wherein thepolymeric barrier environment further comprises an opioid antagonist. 6.The method of claim 1, wherein the biodegradable drug delivery devicefurther comprises a third layer or coating.
 7. The method of claim 1,wherein the polymeric diffusion environment has a pH buffered to betweenabout 4 and about 7.5.
 8. The method of claim 1, wherein the polymericdiffusion environment has a pH buffered to between about 4 to about 6.9. The method of claim 7, wherein the polymeric diffusion environmentcomprises at least one film-forming water-erodible adhesive polymer andat least one bioadhesive polymer.
 10. The method of claim 7, whereinsaid polymeric barrier environment comprises at least one film-formingwater-erodible polymer.
 11. The method of claim 7, wherein the polymericbarrier environment further comprises an opioid antagonist.
 12. Themethod of claim 7, wherein the biodegradable drug delivery devicefurther comprises a third layer or coating.
 13. A device for deliveringbuprenorphine to a subject, the device comprising: a bioerodiblemucoadhesive layer comprising buprenorphine disposed in a polymericdiffusion environment, wherein the polymeric diffusion environment has apH of between about 4 and about 7.5; and a polymeric barrier environmentdisposed adjacent to the mucoadhesive layer, and wherein aunidirectional diffusion gradient of buprenorphine is provided uponapplication to a buccal surface of a subject.
 14. The device of claim13, wherein the polymeric diffusion environment comprises at least onefilm-forming water-erodible adhesive polymer and at least onebioadhesive polymer.
 15. The device of claim 13, wherein said polymericbarrier environment comprises at least one film-forming water-erodiblepolymer.
 16. The device of claim 13, wherein the polymeric diffusionenvironment has a pH of between about 4 and about
 6. 17. The device ofclaim 13, wherein the polymeric barrier environment further comprises anopioid antagonist.
 18. The device of claim 13, wherein the biodegradabledrug delivery device further comprises a third layer or coating.
 19. Thedevice of claim 13, wherein the polymeric diffusion environment has a pHbuffered to between about 4 and about 7.5.
 20. The device of claim 13,wherein the polymeric diffusion environment has a pH buffered to betweenabout 4 to about
 6. 21. The device of claim 19, wherein the polymericdiffusion environment comprises at least one film-forming water-erodibleadhesive polymer and at least one bioadhesive polymer.
 22. The device ofclaim 19, wherein said polymeric barrier environment comprises at leastone film-forming water-erodible polymer.
 23. The device of claim 19,wherein the polymeric barrier environment further comprises an opioidantagonist.
 24. The device of claim 19, wherein the biodegradable drugdelivery device further comprises a third layer or coating.
 25. A methodfor treating pain, the method comprising: adhering a mucoadhesivebiodegradable drug delivery device to a buccal surface of a subject, thedevice comprising: a bioerodible mucoadhesive layer comprising atherapeutically effective amount of buprenorphine for treating paindisposed in a polymeric diffusion environment, wherein the polymericdiffusion environment has a pH buffered to between about 4 and about7.5; and a polymeric barrier environment disposed adjacent to themucoadhesive layer wherein a unidirectional diffusion gradient ofbuprenorphine is provided upon application to the buccal surface.